Method and apparatus for mitigating acute reoxygenation injury during percutaneous coronary intervention

ABSTRACT

A system and methods are described for improving the management of ischemic cardiac tissue during acute coronary syndromes. The system combines a catheter-based sub-system which allows for simultaneous balloon dilation of a coronary artery and infusion of a carefully controlled perfusate during percutaneous coronary intervention. The system allows for modulation of levels of oxygen at the time of percutaneous intervention. In addition, catheters and systems are provided for administration of fluids with modified oxygen content during an intervention that incorporate upstream flow control members to compartmentalize the perfusion of the target coronary artery and the remainder of the heart.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority to U.S. patentapplication Ser. No. 14/802,340, filed Jul. 17, 2015, and titled “Methodand Apparatus for Mitigating Acute Reoxygenation Injury DuringPercutaneous Coronary Intervention,” which is a continuation of andclaims priority to U.S. patent application Ser. No. 14/039,673, filedSep. 27, 2013, and titled “Method and Apparatus for Mitigating AcuteReoxygenation Injury During Percutaneous Coronary Intervention,” whichis now U.S. Pat. No. 9,084,856 issued Jul. 21, 2015, and which is acontinuation of and claims priority to U.S. patent application Ser. No.12/505,309, filed Jul. 17, 2009, and titled “Method and Apparatus forMitigating Acute Reoxygenation Injury During Percutaneous CoronaryIntervention,” which is now U.S. Pat. No. 8,562,585 issued Oct. 22,2013, and which claims priority to U.S. Provisional Application No.61/081,450, filed Jul. 17, 2008. The disclosure of each of the foregoingapplications is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to the clinical arena of interventional cardiologyand, in particular, the field of percutaneous coronary interventions andtreatments for acute coronary syndrome (acute myocardial infarctionand/or unstable angina). A method and apparatus is described thatprovides the operator with an ability to mitigate oxygen-related injuryto a tissue by precisely modulating the level of oxygen re-exposure ofthe tissue at and directly after the time of the intervention. Specificcatheters and systems for administration of fluids with modified oxygencontent during angioplasty procedures are also provided.

BACKGROUND

Considerable effort and resources have been devoted to reducing theburden of cardiovascular disease and mortality rates after acutemyocardial infarction have decreased over the past 30 years. However,coronary artery disease remains the leading cause of morbidity andmortality in the developed world. An estimated 79.4 million Americanadults (1 in 3) have one or more types of cardiovascular disease. Ofthese, an estimated 1.4 million Americans per year will have amyocardial infarction and another 500,000 present with other forms ofacute coronary events that lead to cardiac ischemia. In 2007, anestimated 1.68 million patients were discharged in the US suffering fromacute coronary syndrome. In 2004, an estimated 6,363,000 in-patientcardiovascular operations and procedures were performed in the UnitedStates. These included an estimated 1,285,000 in-patient angioplastyprocedures, 427,000 in-patient bypass procedures and 1,471,000in-patient diagnostic cardiac catheterizations (see Rosamond et al.(2007) Heart Disease and Stroke Statistics—2007 Update. Circulation.115:e69-e171).

For patients who suffer from any form of acute coronary event, the heartmuscle is deprived of adequate levels of oxygen for a variable period oftime and along a range of severity until appropriate treatment can beinitiated. In many cases, irreversible damage to the heart can result ininfarction, with cell death occurring in one of more areas of the leftventricular or right ventricular myocardium or within the conductionsystem of the heart. In addition to the effects of this lack ofavailable oxygen on cardiomyocytes and conduction tissue, it has becomeincreasingly recognized that the endothelial cells lining the bloodvessels (down to the capillary level) can also be damaged or can becomeimpaired in their ability to function even downstream from the immediateinfarction.

For patients with acute coronary thrombosis and infarction, establishedtherapy is timely reperfusion of the culprit coronary artery by openingor bypassing the artery and restoring blood flow to the ischemicterritory. Modern treatment of acute myocardial infarction or myocardialischemia usually comprises performing balloon angioplasty with orwithout stent deployment, directional atherectomy with or without distalprotection or even laser therapy and intracoronary declotting. Suchprocedures can all be broadly considered to be part of the clinicalarena of percutaneous coronary intervention (PCI). Both percutaneousintervention and surgical bypass of the vessels to facilitate increasedblood flow are performed to “salvage” myocardium or other cardiac tissueat risk from further damage by ongoing ischemia that may result in anextension of infarction or new areas of damage. During what could bedefined as the “reperfusion era” it has been observed thatre-establishing proper flow into epicardial coronary arteries: (i)mitigates injury if it is performed in a timely fashion; and (ii)improves survival in large cohorts of patients presenting with theclinical syndrome of myocardial infarction. Simultaneously, however, ithas been observed that in certain circumstances, especially in cases ofprotracted or severe ischemia, reintroduction of blood flow and oxygencan ramp up the injury in a manner consistent with what has beendescribed as reperfusion injury.

In the last several decades, considerable effort has focused on limitinginfarct size and other manifestations of post-ischemic injury. Theconcepts of ischemic pre- and post-conditioning suggest highly evolvedmechanisms by which the heart can protect itself from ischemia undercertain conditions and further investigation points to intracellularsignaling mechanisms that can mitigate injury. In addition, the lastdecade has allowed for a broader understanding of the membrane-boundionic pump disturbances that develop as ischemia progresses and theresultant ionic membrane shifts that are involved in the development ofpost-ischemic contracture when the affected tissue is re-exposed tooxygen containing blood. These disturbances may also point to mechanismsof conduction system dysfunction and/or post-ischemic arrhythmias.

Numerous methods of reducing ischemic insults to tissue, such as throughinterventional catheters that allow infusion of the patient's ownoxygenated blood, have been contemplated. For example, U.S. Pat. No.5,403,274 by Cannon provides an apparatus for passively perfusing bloodpast a stenosis using pressure equalization. U.S. Pat. Nos. 5,573,508and 5,573,509 by Thornton, assigned to Advanced Cardiovascular Systems(ACS), are directed to an intravascular catheter with a perfusion lumenthat can be expanded to increase the flow of oxygenated blood or otherbody fluids when the distal portion of the catheter is occluded. U.S.Pat. No. 5,308,356 by Blackshear provides a passive perfusion catheterwith a balloon that defines at least one passage to permit blood flowwhen the balloon is pressed against the wall of the blood vessel.Similarly, U.S. Pat. No. 5,505,702 by Arney, assigned to Scimed LifeSystems provides a dilation catheter with a composite balloon thatallows passive blood flow past the catheter during dilation. U.S. Pat.No. 5,344,402 provides a low profile drug delivery catheter with atleast one port to permit perfusion of the upstream blood while the drugdelivery balloon is inflated. U.S. Pat. No. 6,302,865 provides aguidewire with a perfusion lumen allowing for perfusion of the arterialblood past an inflated balloon.

To increase blood flow and reduce ischemia, active perfusion cathetershave also been provided that allow perfusion of high oxygen contentfluids past an infarct area. U.S. Pat. No. 5,137,513 by McInnes,assigned to ACS, provides a catheter and method of ‘active’ perfusion,wherein oxygenated blood, preferably from the upstream artery issupplied during inflation of a balloon. Similarly, U.S. Pat. No.5,807,331 by den Heiher and Solar, assigned to Cordis Corp., provides anactive perfusion catheter where blood or other high oxygen contentfluids are perfused past the obstruction during balloon inflation.

Higher oxygen replacement has also been contemplated. For example,European Patent No. 0836495 provides an apparatus for deliveringoxygen-supersaturated solutions during clinical procedures such asangioplasty. Recent clinical trials on such systems have failed to showany significant benefit from the use of supersaturated oxygen therapy.Similarly, U.S. Pat. No. 6,454,997 by Divino et al., assigned to Therox,Inc. provides a high oxygen content fluid through a catheter in anattempt to reduce ischemic injury by combining an oxygen-supersaturatedfluid with patient blood. U.S. Pat. No. 5,186,713 by Raible, assigned toBaxter International, Inc. provides a method and device for the flow ofoxygenated perfusion fluid, preferably the patient's blood, by activeperfusion through an oxygenator.

Although there have been significant advances in reducing ischemia, amajor area of focus has become reducing or even preventing injury thatoccurs after a rapid return of normal blood flow. Typically, coronaryintervention after acute MI involves percutaneous transluminal coronaryangioplasty either with or without subsequent stent deployment. After ashort episode of myocardial ischemia, reperfusion of the area with thepatient's blood results in the rapid restoration of cellular metabolismand function. In clinical situations in which ischemia is moreprotracted or severe, even with the successful treatment of occludedvessels and stenting a serious risk of heart dysfunction and even deathstill exists. If the ischemic episode has been of sufficient severity orduration, reperfusion may, paradoxically, result in a worsening of heartfunction.

Reperfusion injury occurs in tissue when blood supplies return to thetissue after a period of ischemia. The absence of oxygen and nutrientsfrom blood creates a condition in which the subsequent restoration ofcirculation results in inflammation and oxidative damage through theinduction of oxidative stress rather than restoration of normalfunction. This damage is distinct from the injury resulting from theischemia per se. Reperfusion injury may be due in part to theinflammatory response of damaged tissues involving the production ofreactive oxygen species, resulting in: damage to lipid bilayer cellularmembranes; endothelial cell dysfunction; micro-vascular injury;alterations in intracellular Ca²⁺, sodium, potassium and hydrogen ionhomeostasis; changes in myocardial metabolism; and activation ofneutrophils, platelets, and the complement system. In addition, whiteblood cells carried to the area by newly returning blood cause therelease of a host of inflammatory cytokines and other factors such asinterleukins as well as free radicals in response to tissue damage.Under certain conditions, therefore, the restoration of blood flow toischemic tissue exposes the tissue to levels of oxygen that can bedamaging.

Several efforts have been made to reduce reperfusion injuries after PCI.For example, U.S. Publication No. 2006/0258981 by Eidenschink provides acatheter that will reduce the temperature of the surrounding tissue tominimize post-reperfusion injuries. U.S. Publication No. 2006/0100639provides a method and apparatus for treatment of reperfusion injury byaltering blood flow or oxygen delivery after reperfusion of the infarct.

What has typically been overlooked is the possibility of avoidingreoxygenation injury altogether by controlling oxygen deliver during theinitial maneuvers. There remains a need to provide a reliable method ofpreventing post-angioplasty reoxygenation injury.

SUMMARY OF THE INVENTION

In keeping with the foregoing discussion of the molecular mechanisms, itis known that reoxygenation injury can occur after reestablishing bloodflow (perfusion) to a previously ischemic tissue. It has not been widelyappreciated that the severity (intensity and duration) of the antecedentischemic conditions sets the stage for significant oxygen-related damagedepending upon certain conditions that exist at the moment flow isreestablished or ischemia is eliminated. Furthermore, it has not beenappreciated that even a brief period of abrupt oxygen re-exposure toischemic tissue, can initiate damaging oxidative stress, result innumerous inflammatory and gene-related processes and lead to increasedinjury due to ionic imbalances that develop during the ischemic period.Key calcium ion fluctuations or oscillations triggered by the presenceof molecular oxygen that lead to various degrees of contracture can alsooccur. These consequences may be mitigated by avoiding exposure of thetissue at risk to hyperoxygenated (or even relatively hyperoxic)perfusates, which create large tissue oxygen gradients. High oxygengradients have been observed to create a consistent pattern of injuryduring the initial phase of reperfusion/reoxygenation. As such, in oneembodiment of the invention, a method of preventing reoxygenation injuryduring acute PCI is provided comprising administering a modulated oxygencontent fluid during and immediately upon re-opening of an occludedblood vessel in a patient undergoing a coronary intervention. Inparticular, the modulated oxygen content fluid has an initial oxygencontent below that of normal arterial blood. This is specificallycontrasted to any strategy whereby the procedure to open the vesseloccurs first, is completed, and is followed by an attempt to alleviatethe damage already caused by abrupt reestablishment of adequate flow toalleviate ischemic conditions. In one specific embodiment, the coronaryintervention is balloon angioplasty and, in particular, it iscontemplated to provide an angioplasty catheter with an infusion lumenthat is connected to a system that provides inflow of a perfusatecontaining gradually increasing levels of oxygen during the procedure.During this procedure, oxygen delivery to the tissue being treated isguided by a protocol for oxygen reentry that is ramped or increased as afunction of time.

A method is provided of treating a patient undergoing a interventionprocedure in which blood flow to a tissue has been reduced comprisingproviding a catheter comprising an infusion lumen wherein the infusionlumen is designed so as to provide infusion of a fluid to a tissuedistal to an occlusion; inserting the catheter into a blood vessel inwhich blood flow has been reduced; and infusing a modulated oxygencontent fluid through the infusion lumen wherein the fluid comprises anoxygen concentration that is controlled over time, wherein normal bloodflow is not reestablished to the tissue before the infusion. In specificembodiments, the oxygen concentration of the fluid is increased overtime. In specific embodiments, the oxygen concentration of the fluid isinitially lower than the oxygen concentration of blood in the affectedartery, and specifically is lower than a normal oxygen content ofarterial blood.

Furthermore, consistent with a strategy of avoiding any exposure of thetissue at risk to even relatively hyperoxic perfusate, in anotherspecific embodiment a method is provided wherein, during theintervention, an upstream occluding member is attached to a guidecatheter that occludes or blocks the inflow of unmodified blood into thetarget artery to facilitate controlled reoxygenation. Such preciseperfusion is then externally managed via a perfusion device tofacilitate precise operator control of the oxygen partial pressure ofthe perfusate. During such a procedure, an angioplasty catheterincluding an infusion lumen is threaded into a patient's artery,typically using a guidewire and through the introducing lumen of thepreviously described guide catheter. After the balloon is advancedthrough the vessel narrowing, the balloon is inflated against theblockage. Prior to or at the precise moment of inflation of the balloon,the modulated oxygen content fluid administration begins to the patient.In some embodiments, the balloon is inflated prior to administration ofa modulated oxygen content fluid. In certain other embodiments, a fluidis administered prior to inflation of the balloon, in particular a lowoxygen content fluid that can be more consistent with the pre-existentcondition of the tissues in question. In this manner, no highlyoxygenated blood is allowed to perfuse the ischemic tissue and initiatereoxygenation injury, oxidative stress, and explosive oxygen radicalformation, membrane damage in the form of peroxidation of lipidbilayers, deranged calcium flux, contracture or the resultant release ofinflammatory mediators in response to said injury. As the oxygengradient is ramped gradually as a function of time, additional time isprovided for restoration of more appropriate ionic positioning (at thecell membrane and/or within the sarcoplasmic reticular membrane).

In certain embodiments, the partial pressure of oxygen is raisedgradually as a function of time and from as low as 20-30 mmHg of oxygento physiologic oxygen tension of from 60-110 mmHg (or possibly higher)over a period of time that approximates 15-20 minutes. These parametersare intended to be illustrative rather than limiting. The modulatedoxygen perfusate can be administered through an angioplasty catheter ora guide catheter with an upstream occluding member from between aboutfive to about twenty minutes depending of the severity of thepre-existent ischemic conditions. This time frame may be modified todetermine the most appropriate oxygen modulation curve (oxygen partialpressure as a function of time). The ranges and the time frame given areused for illustrative purposes and are not intended to be limiting.

In certain embodiments, the modulated oxygen content fluid is a mixtureof arterial and venous blood and can also include crystalloid solution.In certain embodiments, the mixture is of blood taken from the patientand re-circulated. In some embodiments, the blood is initially venousblood. In some embodiments, arterial blood is added to the venous bloodto result in various ratios of venous (deoxygenated) to arterial(oxygenated) blood in a time frame consistent with that stated abovestarting from the time of the initial balloon inflation or just priorupon engaging the target artery. In certain other embodiments, the ratioof arterial blood is increased in a stepwise fashion so that, at the endof a specified time frame, only arterial (oxygenated) blood isadministered. In some embodiments, the degree of oxygenation of arterialblood is increased steadily as a function of time so that only arterialblood is administered but with a gradually increasing oxygen partialpressure.

In certain embodiments, the method further comprises placing an oxygensensor distal to the catheter to ensure the accuracy of the oxygendelivery. In certain embodiments, the oxygen sensor can be on aguidewire. In certain other embodiments, the catheter additionallycomprises an oxygen sensor at the distal tip of the balloon. In certainembodiments, the sensors are not in the patient's body but are external,for example as part of the oxygenation system.

In some embodiments, the oxygen content of the fluid is modulated by useof an oxygenator. In certain embodiments, the fluid is a low oxygencontent fluid such as venous blood and the content of oxygen isincreased, such as through an oxygenator. In some other embodiments, theoxygen content is regulated by at least one deoxygenator. In certainembodiments, the initial fluid is a high oxygen content fluid such asarterial blood and the content of oxygen is reduced.

In certain embodiments, the oxygenator is controlled by at least onemicroprocessor. In some embodiments, the oxygen content is modulatedbased on a preset program that may be overridden manually by theoperator. In yet other embodiments, the oxygen content is controlled bythe user. In certain other embodiments, at least one microprocessorreceives data from oxygen sensors and adjusts a pump or an oxygenator orboth to adjust the flow or oxygenation content of an infusion fluid andregulate the content of oxygen in the infusion fluid to correspond to aprogrammed set point.

In certain of these embodiments, a sensor provides a baseline reading ofblood flow or oxygen content in the vessel that is used to generateinitial parameters for oxygen content. In certain embodiments, theinitial oxygen content in the infusion fluid is at or above the contentof blood flow or oxygen measured prior to commencement of the PCIprocedure. In certain other embodiments, the initial oxygen content inthe fluid is at or below the content of oxygen measured prior tocommencement of the PCI procedure. In certain other embodiments, thelength of time of infusion of modulated oxygen content fluid isdependent on the level of blood flow or oxygen content of the infusionfluid as measured prior to commencement of the PCI procedure.

In certain embodiments, the oxygen content in the perfusate fluid isassigned based on the content of oxygen needed in the vessel, which canbe provided by sensors that can provide a starting point for therapy.The oxygen content can be measured either by analyzing the partialpressure of oxygen in the blood, or by measuring the oxygen saturationof the patient's hemoglobin. In one non-limiting embodiment, the partialpressure of oxygen can be ramped up 1 mmHg at a time every 15-60 secondsand from approximately 20 mmHg to as high as 90-110 mmHg over a 5-20minute time frame depending on initial conditions and/or the judgment ofthe operator.

In another embodiment a patient's blood may be rerouted to a heart lungmachine, mini-heart lung machine or cardiopulmonary bypass circuiteither with or without the capacity for an oxygenator or separatecardioplegia circuit. As such, wherein the heart's workload isdiminished and therefore the minute-to-minute oxygen demand of the heartis limited, these maneuvers may also effect changes in the overallsupply-demand balance of oxygen to the heart and may, by itself, limitor eliminate the ischemic conditions.

In some embodiments, the sensor measures the oxygen content of alocation distal to the catheter, such as the coronary sinus. In otherembodiments, the sensor measures oxygen content of a location not distalto the catheter. In certain embodiments, a ratio of oxygen content inblood distal to and not distal, especially proximal, to the catheter ismeasured and that ratio provides the basis for setting the initialoxygen content in the perfusion fluid and may suggest alterations inideal time frame of the change in oxygen as a function of time or mayprompt a change in the starting point for the partial pressure of oxygenin the initial perfusate.

In still other non-limiting embodiments, parameters other than oxygenare not modulated over time. The temperature of the fluid can be atnormal physiologic body temperature of the patient (normothermic). Incertain non-limiting embodiments, the procedure is conducted during PCInot associated with a cardiopulmonary bypass. In some embodiments, theprocedure can be conducted without the patient's arterial blood beingrerouted from the body. In specific embodiments, the patient has afunctioning heart and lungs. Typically, a cardioplegia solution is notadministered to the tissue before balloon inflation.

In some embodiments, the fluid is infused directly through a pump thatcan be free-standing from any extracorporeal circuit. In otherembodiments, the fluid is infused from a reservoir that may beintegrated into a cardiopulmonary bypass circuit. In certainembodiments, the pump is regulated by a controller. The controller canbe programmable. In certain embodiments, the controller sets infusionparameters based on measurement of a patient parameter.

In certain embodiments, the balloon completely occludes blood flow inthe artery. The balloon is typically inflated only once, and no arterialblood is initially allowed to pass beyond the balloon. In someembodiments, the catheter includes only a single balloon.

The method can further comprise inserting a stent into the artery. Thestent can be inserted after infusion of the modified oxygen perfusate.In another embodiment the stent is inserted prior to the infusion of themodified oxygen perfusate. As such the stent can be positioned on theballoon and inserted during dilatation and infusion of the modifiedoxygen perfusate. In another embodiment the stent is positioned on asecond catheter and not deployed until after the controlledreoxygenation is completed. In another embodiment, the infusion isbefore placement of a stent. The stent can thus be inserted afterarterial blood has been reintroduced into the area distal to thecatheter but not before the operator has had the opportunity to performthe controlled oxygen procedure for the purpose of rescuing the tissueat risk.

In particular embodiments of the invention, the host or subject to whichthe method and system is applied is a human. In specific embodiments,the host is a human who is in need of prevention of reoxygenationinjury. In certain embodiments, the host is a human patient withcardiovascular disease.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic of the method of the invention.

FIG. 2 provides a proposed oxygen delivery graph, based on differentinitial ischemia levels

FIG. 3 is a schematic of a perfusion control apparatus for use in theinvention.

FIG. 4 is a diagram of a perfusion catheter system that can be used forthe invention.

DETAILED DESCRIPTION

In a first exemplary embodiment a method of preventing post-PCIreoxygenation injury is provided comprising administering a modulatedoxygen content perfusate during the intervention. The method can be usedfor performing a percutaneous coronary intervention during an acutecoronary syndrome or myocardial infarction in which it is recognizedthat a variable degree of ischemia is present. In particularembodiments, the method can be used when it is recognized that theischemic tissue must be managed carefully and attended to differentlythan in more elective interventions. The invention can be used eitherduring an acute coronary event or in conjunction with PCI related to achronic obstruction. In specific embodiments, the coronary interventionmay be percutaneous transluminal coronary balloon angioplasty (a type ofPCI), coronary atherectomy and/or deployment of a coronary stent. Asshown in FIG. 4 in particular, it is contemplated to provide anangioplasty catheter with an infusion lumen that is connected to asystem that provides inflow of an increasing content of oxygen duringthe angioplasty procedure.

In a typical PCI procedure, the physician uses local anesthetic to numba specific area of the patient's body, usually the upper thigh areawhere the femoral artery is located. A small tube called a sheath isinserted into an artery, such as the femoral artery. A flexibleballoon-tipped plastic catheter approximately 2 mm in diameter and 80 cmlong is inserted through the sheath, advanced to the heart and directedto an area of coronary blood vessel narrowing. The balloon mounted onthe tip of the catheter is introduced into the coronary artery until ittraverses the thrombus and/or occlusion. The balloon is inflated to apressure of typically 6-8 atmospheres. The balloon expands and enlargesthe artery by compressing the thrombus material and/or plaque andopening the coronary artery. For an artery having a 3 mm nominaldiameter, the balloon is expanded to 2.7 to 3.3 mm diameter by inflationto a “nominal” balloon pressure. The inflation of the balloon isactuated by a control console that is external to the patient andconnected to the catheter. Manufacturers of angioplasty balloons supplypressure vs. diameter compliance curves to physicians. When the ballooninflates, it displaces the blockage against the vessel wall and reopensthe vessel. The same catheter that is used to open the occluded coronaryartery is used to control blood flow to the distal branches of thecoronary artery and the zone of infarct. With the blood flow restored,the balloon catheter is then deflated and removed.

It is conventional during acute PCI (PCI performed during an acutecoronary event) that after the inflation of the balloon, the physicianrapidly deflates the balloon and removes it from the coronary arteryquickly to allow blood flow to the distal coronary branches and to thezone of the heart muscle that may already have infarcted areas(non-contracting, necrotic tissue that will be replaced by scar tissue)and tissue that is not yet infarcted but is ischemic and at risk ofinfarct. In the prior art, such perfusion with unmodified blood afterthe abrupt opening of an obstruction rushes to the tissue at risk ofinfarction and may cause reperfusion injury with a component ofreoxygenation injury; depending upon the antecedent ischemic conditions.

Similarly, coronary artery stenting is a catheter-based procedure inwhich a stent (a small, expandable wire mesh tube or scaffolding) isinserted into a diseased artery to hold open the artery. Its most commonuse is in conjunction with balloon angioplasty to treat coronary arterydisease. After the angioplasty balloon reduces the narrowing of thecoronary artery, the stent is inserted to prevent the artery fromre-closing. Stents are left in place in the artery. In the setting of anacute MI and acute PCI, angioplasty pre-dilatation is always performedbefore stenting. In this exemplary embodiment the balloon pre-dilatationis linked by way of a specialized flow catheter to provide a controlledoxygen content perfusate prior to stent deployment.

In one embodiment, a balloon tipped catheter may be used both as anangioplasty dilation balloon and to provide a modulated oxygen contentfluid to the area distal to the catheter during the procedure. Theballoon can be, for example, positioned inside the narrowed or occludedcoronary vessel at the site of the coronary lesion. At the time theballoon is inflated a concomitant interruption of already diminishedblood flow in the coronary artery supplying the heart muscle at risk ofreoxygenation injury occurs. In the prior art this was viewed primarilyas an issue leading to a brief period of additional ischemia. However,this invention mitigates over-exposure to abrupt oxygen gradients andreduces injury by allowing for immediate initiation of carefullycontrolled blood flow with a modified oxygen content fluid.

An embodiment of a process of the invention is shown in FIG. 1. Thephysician inserts a guidewire into the artery past the blockage. Theguidewire tip can either include a probe or sensor that can measureoxygen content, or the physician can already have used other means toassess the extent of ischemia in the area. In certain instances, thephysician cannot appropriately assess the level of ischemia and mustbase the content of oxygen and fluid levels to be given to the patientbased on a standard model. In either case, an oxygen curve is calculatedfor the patient that includes the starting content of oxygen in theperfusate, the final levels, the time course over which the content willbe increased and whether this will be in a stepwise, linear, curvilinearor smooth fashion. These examples are provided to be illustrative ratherthan limiting. After analysis of the oxygen content of the fluid andcalculation of the oxygen curve, a balloon catheter is inserted over theguidewire. At this stage it may be beneficial to measure oxygen contentdistal to the balloon to refine the initial setup of the oxygen deliverycurve. After the final oxygen delivery curve is calculated, the balloonis inflated and perfusion with the modulated oxygen content fluid isbegun. After the oxygen perfusion curve is finalized, the balloon isdeflated and the catheter removed.

Modulated Oxygen Content Fluid

The invention provides prevention of reoxygenation injury specificallyby modulating the exposure of the ischemic tissue to oxygen during acutepercutaneous coronary intervention. In contrast, the prior artenvisioned allowing arterial and relatively hyperoxic blood to perfusethe distal artery after ischemia for at least some period of time priorto infusing a modified fluid.

A modulated oxygen content fluid is one in which the fluid comprises anoxygen partial pressure or oxygen concentration that changes over time.In particular embodiments, the oxygen content of the fluid is increasedover time. The oxygen level or concentration can increase gradually, orincrease in graduated steps. In certain embodiments the amount of oxygendoes not rise steadily, but at times either remains constant or islowered, for example to accommodate the needs of the patient. Themodulated oxygen content fluid can be blood or can be any otherphysiologically acceptable solution, such as a supplemented saline,blood plasma, lactate solution, Ringer's solution, venous blood, amixture of deoxygenated, such as venous and oxygenated, such as arterialblood, or a mixture of blood and a suitable physiologic solution similarin composition to blood plasma, water, a cardioplegia crystalloidsolution, or other buffered solution. In certain embodiments, themodulated oxygen content fluid is not made by mixing deoxygenated andoxygenated blood. In this embodiment, the fluid can be oxygenated bloodor a blood substitute mixed with a low-oxygen blood additive. The fluidcan also be blood that is oxygenated to the desired oxygen content.

In some embodiments, the modulated oxygen content fluid flows throughthe vascular system passively, through a pressure gradient. In otherembodiments, the fluid is actively perfused by a pump, the fluid flowrate of which can be varied.

In certain non-limiting embodiments, the oxygen content of the fluid isincreased from 1% of the oxygen content of the arterial blood to 100% ofthe oxygen content of arterial blood over the course of the procedure.The procedure can be from one to sixty minutes or more. In someembodiments, the procedure is carried out over about sixty minutes orless, for example over about 40, about 30, about 20, about 15 or about10 minutes. In other embodiments, the oxygen content is increased from5% to 75% over the course of thirty minutes. In yet another non-limitingembodiment, the oxygen content is increased from 5 to 50% over thecourse of twenty minutes.

In certain non-limiting embodiments, oxygen content is increased in astepwise fashion. For example, the modulated oxygen content fluid can,at time t₀ be less than 50% oxygen saturation, such as less than 20%.This level of oxygen can be perfused for a period of time to t₁. Thefirst period can be about 15 minutes, or it can be less such as forexample ten, nine, eight, seven, six, five or less minutes. At time t₁,the content of oxygen can be increased to about 50%, such as between 40and 60% up until time t₂. The second period can be approximately 15minutes, or can be less, such as for example ten, nine, eight, seven,six, five or less minutes. At time t₂, the content of oxygen can beincreased to about 75%, such as between 60 and 80% up until time t₃. Thethird period can also be approximately 15 minutes, or can be less, suchas for example ten, nine, eight, seven, six, five or less minutes. Attime t₃, the content of oxygen can be increased to levels approximatingarterial blood. In certain instances, at t₃, the balloon is deflated andarterial blood is allowed to perfuse the area.

Some illustrative embodiments of a modulated oxygen contentadministration curve are presented in FIG. 2. In embodiments, such aswhen ischemia is minor, very low levels of oxygen are not necessary forextended periods of time. In those instances, the initial curve canbegin at approximately 20 mmHg and rapidly rise, for example within 5minutes or less. In other instances, such as if ischemia is severe, lowlevels of oxygen should be provided for at least 5 or at least 10minutes.

The balloon can be gradually deflated to gradually allow the flow of thenormal arterial blood to be mixed with the oxygen poor perfusate comingout of the tip of the catheter. If the coronary artery is not occludedby the balloon at the end of therapy all the blood flow to the infarctzone will come from natural perfusion of the heart with arterial blood.

The perfusate in which oxygen is regulated can be leukocyte-depletedblood of the same patient or a donor. In one embodiment, blood will beremoved from the patient, put though a filter that removes a significantportion of the leukocytes, in certain cases neutrophils, and then usedto perfuse the area distal to the tip of the catheter. In oneembodiment, blood may be withdrawn from the sheath used for arterialaccess but may be withdraw from the patient using any other method ofarterial or venous access that will provide the desired blood flow forperfusion. The mode of withdrawal may be using gravity or a pump as longas the desired blood flow is achieved. The blood is then passed though aleukocyte-removal filter to remove a clinically advantageous amount ofleukocytes from the blood. An example of one such filter is theCellsorba-80P (Asahi Medical Co).

Oxygen content of the blood or perfusion fluid can be read by sensorsthat may take a variety of forms. For example, the oxygen content maycomprise partial pressure of oxygen (pO₂) or the percentage of oxygensaturation (O₂ saturation). Alternatively, the sensors may measure bothpO₂ and the O₂ saturation. In yet another embodiment, the coronaryperfusion device addresses oxygen content by considering the totalamount of oxygen content in the fluid. Any of these measurements for thepurposes of the current application can be considered to represent an“oxygen content.” In this regard, non-limiting alternative embodimentsmay evaluate oxygen content by evaluating pO₂, O₂ saturation, hemoglobinlevel, and/or the amount of oxygen dissolved in the blood.

As one skilled in the art would appreciate, the oxygenator may takeseveral different forms. For example, the oxygenator may be a bubble ormembrane oxygenator. Similarly, the pump may comprise a variety ofdifferent types of pumps. For example, a roller pump or centrifugalpump, in which the speed of the spinning head (and the resistance of thesystem) determines the flow of blood or perfusate, a piston-basedarrangement that may affect flow by the application of pressure ontopreviously described bladder reservoirs, or any now known or laterdeveloped device suitable for controlling the flow of fluids may beused.

Typically, the content of oxygen is regulated in the circuit through anoxygenation controller. The oxygenation controller typically includesone or more selected from a microprocessor, a general processor, acontroller, an application specific integrated circuit, a transistor, afield programmable gate array, an analog circuit, a digital circuit,valves, pumps, filters, tubing, a reservoir, a bladder, a series ofreservoirs or bladders, relays, sensors, and pulse oximetry sensors,combinations thereof or other now known or later developed devices formixing fluids from two different sources by using data relating topartial pressure of oxygen, oxygen saturation, or oxygen content in thefluids. In certain embodiments, the oxygenation controller regulatesoxygen content based on a preset automatic or manually entered protocol.

The oxygenation controller allows the operator to adjust the oxygencontent of the blood sent through the catheter. In one embodiment, theoxygenation controller includes a dial for adjusting the outputoxygenation content and a real-time display for parameters such asoxygen saturation and partial pressure of oxygen (pO₂). In otherembodiments, the oxygenation controller may include one or more of avariety of different input devices, including buttons, knobs, a mouse, atrackball, sliders, touch pads, sensors or touch screens, to controlparameters of the output blood. The oxygenation controller can also bepre-set to run a particular protocol automatically. In some instances,the controller running a pre-set protocol can be regulated by externaldata such as data from sensors. In particular embodiments, thecontroller is automatically pre-set based on initial patient parameters(such as physical characteristics (height, weight, etc.), measuredischemia, clinical symptoms, or the like) but the protocol isautomatically adjusted. In certain embodiments, the controller haspre-set a number of perfusion protocols that are automatically selectedbased on certain patient parameters, such as those above or others yetto be identified.

In some instances, the modulated oxygen content fluid is prepared bymixing oxygenated blood, which can be aortic or prepared by use of anoxygenator, with a physiologic fluid such as normal saline that containsno oxygen. In certain embodiments, the modulated oxygen content fluid isprepared using procedures such as described in U.S. Patent ApplicationNo. 2005/0084416, which is incorporated herein. A half blood-half salinemix will produce approximately 45-50% oxygen saturation in theperfusate. Mixing can be accomplished outside of the body or inside ofthe body by adding known amount of saline to the blood inside thetargeted coronary artery. For example if blood flow in the coronaryartery is 50 ml/min, infusing 25 ml/min of saline into the artery willresult in approximately 50% reduction of oxygen delivery to the infarctzone. In some embodiments, the oxygenation controller mixes oxygenatedand deoxygenated blood in a ratio that results in a controlled oxygensaturation and pO₂ level before delivery of the mixed blood through thecatheter. In this embodiment, the oxygenation controller can include twoinputs: an oxygenated blood input and deoxygenated blood input, whichcan come from the venous supply. The oxygenated blood input receivesoxygenated blood directly or indirectly from the oxygenator. The oxygenpartial pressure and saturation levels are measured by a sensor. Thedeoxygenated blood input directly or indirectly receives blood that wascollected in the venous reservoir. The oxygen partial pressure andsaturation levels of this blood are also measured by a sensor. A pumpcan control the flow of both oxygenated and deoxygenated blood to areservoir.

Oxygen Content

In certain embodiments, the oxygen content in the fluid is controlled byat least one microprocessor. The microprocessor can receive data fromsensors, pumps, and a perfusion control input. The microprocessor can bea digital signal processor, application specific integrated circuit, afield programmable gate array, a control processor, an analog circuit, adigital circuit, a network, combinations thereof or other now known orlater developed device for controlling a mixing ratio.

Sensors can provide the microprocessor with data about the level ofoxygen of the fluids being administered. In certain other embodiments,at least one microprocessor receives data from the sensors and controlspumps that adjust the flow of an oxygenated fluid to regulate the oxygencontent in the infusion fluid.

The sensors can also provide information on parameters other than oxygencontent. In one embodiment, the sensors provide information on levels ofocclusion. This can be measured using, for example, ultrasound, Doppler,or pressure sensors, among others. In other embodiments, the sensors canprovide information on additional blood constituents.

In some embodiments, an oxygen sensor is placed at the site of narrowingprior to placement of the catheter. In certain of these embodiments, thesensor provides a baseline reading that is used to generate initialparameters for oxygen content. In certain embodiments, the initialoxygen content is at or above the content of oxygen measured prior tocommencement of the PCI procedure. In certain other embodiments, theinitial oxygen content is at or below the level of oxygen measured priorto commencement of the PCI procedure. In certain other embodiments, thelength of time of infusion of modulated oxygen content fluid isdependent on the level of oxygen measured prior to commencement of thePCI procedure.

In certain other embodiments, a sensor measures the level of occlusionof an artery prior to intervention. In certain embodiments, thepercentage occlusion provides a baseline reading used to generateinitial parameters for oxygen levels. In certain other embodiments, thelevel of occlusion is used to regulate the length of time of infusion ofthe modulated oxygen content fluid. In some embodiments, the level ofocclusion is measured using ultrasound. In other embodiments, the levelof occlusion is measured by Doppler flow. In still other embodiments,the occlusion is measured using a pressure sensor, such as a sensor ormeter on the catheter.

Additionally, other sensors may be added to incorporate measurement ofother parameters of the deoxygenated blood, oxygenated blood, modulatedoxygen content fluid, or the overall mixture provided to the perfusionpathway. The sensors may be in a variety of locations. For example,sensors may be located in reservoirs, pumps, or tubing. A fewer numberof sensors may be used, such as only one sensor at an output of the mixor two sensors at the two inputs without a sensor at the output.

In certain embodiments, the level of oxygen in the tissue is measuredbefore perfusion and the oxygen content in the fluid is set based on thelevel of oxygen in the tissue. In furtherance of this embodiment, thepartial pressure of oxygen provokes a microprocessor response thatcauses a gradual ramping up of the oxygen content in the perfusate overtime. In certain embodiments, the oxygen content is measured bymeasuring the partial pressure of oxygen. In some embodiments, abruptchanges to the pO₂ and a gradient beyond 20 mmHg is not allowable forthe first 20 minutes of the therapy. After the first twenty minutes thegradient is allowed to widen; however other embodiments provide for useof this device platform to perform research to further elucidate theoptimal gradients and the optimal time frames and function curves ofchange of pO₂ as a function of time.

In some embodiments, the sensor measures the oxygen content of blooddistal to the catheter. In other embodiments, the sensor measures oxygencontent of blood not distal to the catheter. In certain embodiments, aratio of oxygen levels in blood distal to and not distal, especiallyproximal, to the catheter is measured and that ratio provides the basisfor setting the initial levels and infusion parameters of the perfusionfluid.

The sensors may be constructed using fiberoptics for oximetry readings,continuous blood gas analysis, or any other method in which bloodchemistry levels, such as pO₂ or oxygen saturation, may be obtained. Aperfusion control, such as a memory, processor, data base, user inputdevice or a data port, allows a perfusionist to control the oxygenpartial pressure and saturation levels. Typically, the microprocessoralso includes a display. The perfusion control provides themicroprocessor with the desired parameters. Utilizing the data receivedfrom the sensors, the microprocessor can control pumps regulatingmodulated oxygen content fluid to insure that the desired oxygen contentof the output is achieved. The display is usually a monitor, CRT, LCD,projector, LED or other now known or later developed display device. Thedisplay may provide data on the input and output oxygen content, bloodflow rates, pressure levels or combinations thereof.

One non-limiting embodiment of a mechanism by which the oxygen levelscan be regulated is shown in FIG. 3. In this embodiment, the oxygencontent in the blood or blood substitute as well as any blood additive(such as saline) are measured. These are compared to a desired bloodinput curve. If the levels of the perfusate are those desired, nofurther adjustments are made to the perfusate. If the levels do notmatch the desired level, the system adds oxygen through an oxygenator ordeoxygenates the perfusate either through, for example, a filter orreduces oxygen concentration by dilution through addition of low oxygencontent fluid such as saline, and mixes this modulated fluid into theperfusate reaching the patient until desired levels are achieved in theperfusate reaching the tissue.

In addition, catheters and systems are provided for administration offluids with modified oxygen content during an intervention thatincorporate upstream flow control members to compartmentalize theperfusion of the target coronary artery and the remainder of the heart.In certain embodiments, the flow control members limit the flow ofarterial blood into a target blood vessel. In specific embodiments, theupstream flow control members regulate the flow of oxygen modulatedfluid into the blood vessel distal to an occlusion. In specificembodiments, the flow control members limit the flow of hyperoxygenatedfluid, including arterial blood, into hypoxic tissues, in particularinto areas around the occlusion.

In yet another embodiment, the microprocessor may control a timingmechanism that gauges the time frame in which specific levels ofoxygenation (or other parameters) occur. Alarm mechanisms may also beincorporated to send a warning to the perfusionists or operatorconcerning whether input or output blood levels are low, whether theoxygen content is too high or too low. The alarms can be controlled bythe microprocessor based on the sensor or other information received anddisplayed on the display. Additionally, another microprocessor maycontrol the operation of the oxygenation controller.

Types of Catheters

Typically an angioplasty catheter includes a perfusion lumen. Thecatheter can be any of a variety of perfusion catheters known in theart, such as those used to infuse drugs, blood and blood substitutesinto the blood vessels of the heart. Suitable catheters include, forexample, those described in U.S. Pat. No. 5,833,659, to Cordis, whichdescribes an apparatus and method is disclosed relating to a rapidexchange perfusion and infusion balloon catheter for treating a bloodvessel with a treatment fluid; U.S. Pat. No. 5,823,996 to Cordis, whichprovides an infusion catheter with a passageway in the catheter bodyextending to an infusion device which has inner and outer chambers withholes in a wall that route the solution into a subject vasculature; U.S.Pat. No. 5,403,274 by Cannon, which provides an apparatus for passivelyperfusing blood past a stenosis using pressure equalization; U.S. Pat.Nos. 6,302,865 and 5,797,876 to Spears, which provide guidewires with aperfusion lumen allowing for perfusion of the arterial blood past aninflated balloon; U.S. Pat. No. 5,137,513 by McInnes, assigned to ACS,which provides a catheter and method of ‘active’ perfusion; U.S. Pat.No. 5,807,331 by den Heiher and Solar, assigned to Cordis Corp., whichprovides an active perfusion catheter where fluids are perfused past theobstruction during balloon inflation; U.S. Pat. No. 5,318,531, whichprovides a balloon catheter in which the balloon comprises a pluralityof holes to permit medication delivered through the lumen to passoutwardly through the holes; European Patent No. 0836495, which providesan apparatus for delivering oxygen-supersaturated solutions duringclinical procedures such as angioplasty; U.S. Pat. No. 5,186,713 byRaible, assigned to Baxter International, Inc. provides a method anddevice for providing flow of oxygenated perfusion fluid, preferably thepatient's blood, by active perfusion through an oxygenator; U.S.Publication No. 2006/0258981 by Eidenschink, which provides a catheterthat will reduce the temperature of the surrounding tissue to minimizepost-reperfusion injuries; and U.S. Publication No. 2006/0100639, whichprovides a method and apparatus for treatment of reperfusion injury byaltering blood flow or oxygen delivery following reperfusion of theinfarct.

A catheter can be equipped with a balloon used to isolate the distalsection (branches) of the coronary artery that perfuse the infarct area.The perfusate is discharged from the distal end of the catheter.Standard perfusion means such as hydration or electronic IV infusionpumps, pressurized IV bags or motorized syringe fluid delivery systems,blood pumps such as cardioplegia pumps and heart lung bypass machines,or regulated systems such as those described herein above can be used toperfuse the infarct zone for up to 20 or up to 30 or up to 40 or up to50 or up to 60 minutes following the opening of the artery. Typically, aperfusate flow of less than 100 ml/min will be sufficient.

In some embodiments, a perfusion catheter can be used which includes atleast two balloons. In a non-limiting example of this use, both balloonsare inflated. The distal balloon can thereafter be deflated to allowslow perfusion of the tissue distal to the occlusion. The perfusate isthereafter infused between the proximal and distal balloon.

This disclosure has been presented in the context of coronaryinterventions, however these techniques are equally applicable tonon-coronary interventions such as peripheral interventions,brain-related interventions such as in cases of stroke or othercerebrovascular disorders, or any other interventions in which ischemictissue will be exposed to oxygenated fluids.

It will be apparent to one of skill in the art that the embodimentsprovided are merely exemplary, and that the invention should not be solimited. Accordingly, those of skill in the art will recognize variousalternative designs and embodiments for practicing the invention.

The invention claimed is:
 1. A reperfusion system for use in treating apatient undergoing an interventional procedure in which a blood flow toa tissue has been reduced comprising: a catheter having an occludingmember; and an oxygenation controller in fluid communication with thecatheter, the oxygenation controller comprising: a pump for forcing aperfusate through the vascular perfusion catheter; a perfusateoxygenation modulator for controlling the oxygen level within theperfusate, and a controller configured to change the oxygenation levelwithin the perfusate from a first oxygenation level to at least a secondoxygenation level, the second oxygenation level being different from thefirst oxygenation level.
 2. The system of claim 1 further comprising anoxygen sensor in electrical communication with the controller.
 3. Thesystem of claim 1 wherein the controller controls the oxygen level inthe perfusate from a 1% oxygen level to an oxygen level below the oxygenlevel of venous blood.
 4. The system of claim 1, further comprising anoxygen sensor in electrical communication with the controller, theoxygen sensor sensing an actual oxygen level, the controller comparingthe actual oxygen level to the instantaneous oxygenation level.
 5. Thesystem of claim 1, further comprising at least two reservoirs, eachreservoir suitable for containing a perfusate component and connected tothe pump, the oxygen level being regulated by selecting an appropriateratio of perfusate components.
 6. The system of claim 5, wherein atleast one reservoir contains oxygen.
 7. The system of claim 5, whereinthe perfusate components can create a perfusate having an oxygen levelless than that in arterial blood.
 8. The system of claim 5, wherein thecontroller controls the pump such that the perfusate is pumped at aconstant flow rate.
 9. The system of claim 1, further comprising aballoon catheter, the balloon catheter and the catheter cooperate suchthat when the balloon catheter is inflated, an opening of the catheterwill be downstream of the inflated balloon catheter.
 10. The system ofclaim 1, wherein the controller includes a processor.
 11. The system ofclaim 1, wherein the controller regulates the oxygen level in theperfusate from an oxygen level consistent with venous blood to an oxygenlevel consistent with arterial blood.
 12. The controller of claim 1,wherein at least some of at least two reservoirs contain perfusatecomponents suitable to create a perfusate having an oxygen levelconsistent with venous blood to an oxygen level consistent with arterialblood.
 13. The system of claim 1, further having electronically storedtherein a plurality of treatment protocols for tissues having variousinitial levels of ischemia, each treatment protocol defining anintentional change in oxygenation level over time of the perfusate for atissue having a specific initial level of ischemia, and programming toselect one of the electronically stored plurality of treatment protocolsbased on the inputted tissue's initial level of ischemia and to controlthe perfusate oxygenation modulator to render the selected treatmentprotocol.
 14. An oxygenation controller for use in treating a patientundergoing an interventional procedure in which a blood flow to a tissuehas been reduced comprising: a pump for forcing a perfusate through acatheter having an occluding member; a perfusate oxygenation modulatorfor controlling the oxygen level within the perfusate, and a controllerconfigured to change the oxygenation level within the perfusate from afirst oxygenation level to at least a second oxygenation level, thesecond oxygenation level being different from the first oxygenationlevel.
 15. The controller of claim 14, further comprising at least tworeservoirs, each reservoir suitable for containing a perfusate componentand connected to the pump, the oxygen level being regulated by selectingan appropriate ratio of the perfusate components.
 16. The controller ofclaim 15, wherein at least one reservoir contains oxygen.
 17. Thecontroller of claim 14, further comprising at least two reservoirs, eachreservoir containing a perfusate component suitable to create aperfusate having an oxygen level less than that in venous blood.
 18. Thecontroller of claim 14, further comprising at least two reservoirs, eachreservoir containing a perfusate component suitable to create aperfusate having an oxygen level from less than 1% to an oxygen levelbelow the oxygen level of venous blood.
 19. The controller of claim 14,wherein the controller controls the pump such that the perfusate ispumped at a constant flow rate.
 20. The controller of claim 14, whereinthe controller includes a microprocessor.